1. Field of the Invention
The present invention relates to novel quinoline-4-carbonylguanidine derivatives or pharmaceutically acceptable salts thereof. More specifically, the present invention relates to an agent which contains the above-mentioned compounds and which is particularly useful as an inhibitor of an Na.sup.+ /H.sup.+ exchanger (hereinafter referred to as "NHE") for treating or preventing hypertension, arrhythmia, myocardial infarction, angina pectoris, arteriosclerosis, diabetic complication, fibrosis of lung, liver, kidney and the like, cell growth of vascular smooth muscle, cardiac muscle, prostate and the like, and cancers, a protective solution of internal organs cut from the body for transplantation or internal organs transplanted, and a diagnostic agent.
2. Description of the Related Art
It has been known that when the pH in cells changes, the activity of enzymes or ion channels in cells also changes, which greatly influences physiological functions of the cells. Accordingly, a mechanism of regulating an intracellular pH has been long studied, and the presence of various ion exchangers that contribute to maintenance of homeostasis of an intracellular pH in cells has been clarified. NHE is one of these systems, and a variety of physiological functions such as regulation of a pH in cells, cell volumes, cell growth and the like have become known. In recent years, it has become clear through experiments that hormones, growth factors and intracellular acidosis activate NHE and result in a cytoplasmic alkalinization [Cir. Res., 57, 773-788 (1985)]. These NHE activators attract attention as factors that cause various diseases, and studies for clarifying the relationship between enhanced NHE activity and these diseases are now assiduously being conducted. With respect to study reports concerning NHE, there are general reports, such as Cir. Res., 57, 773-788 (1985) and Hypertension Hypertension, 21, 607-617 (1993).
Recently, it has been reported that NHE is activated in myocardial ischemia and reperfusion [Cir. Res., 66, 1156-1159 (1990)], and that inhibition of NHE is effective for preventing disorders caused by myocardial ischemia and the consequential arrhythmia [Cir. Res.,73, 269-275, (1993)]. Accordingly, the NHE inhibitor is useful for preventing or treating angina pectoris and myocardial infarction, ischemic arrhythmia, reperfusion arrhythmia, organ disorders following ischemia and reperfusion, cerebral ischemic disorders, cerebral apoplexy and ischemic diseases of limbs and peripheral organs. Further, it is useful as an agent for myocardial protection and organ protection under anoxic condition and reperfusion state in surgical operation or transplantation of internal organs, or as an ingredient of a protective solution for treating or preventing disorders of internal organs cut from the body for transplantation or internal organs transplanted.
The relationship between NHE activity and hypertension has attracted attention so far. Recently, hyperfunction of NHE has been observed in cells such as platelets, erythrocytes, leukocytes and the like of patients suffering from essential hypertension [Hypertension, 21, 607-617 (1993)], and the relationship between NHE and hypertension has been clarified.
Further, it has been reported that in many cells, NHE participates in cell growth through inclusion of Na.sup.+ into cells and intracellular alkalinization, and that amiloride having NHE inhibitory activity suppresses cardiac hypertrophy [Circulation, 86 ( Suppl. I) I -177 (1992)]. That is, it is suggested that the NHE inhibitor is useful as an agent for preventing or treating diseases caused by excessive cell growth with an enhanced NHE activity, such as arteriosclerosis, vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA) associated with a proliferation of vascular smooth muscle cells, rheumatoid arthritis with a proliferation of synovial cells, renal glomerulosclerosis with a proliferation of mesangial cells, pulmonary, hepatic and renal fibrosis with a proliferation of fiblobrasts, diabetic complication caused by vascularization, cardiac hypertrophy, prostatic hypertrophy and the like, and cancers [Cir. Res., 57, 773-788 (1985), Proc. Natl. Acad. Sci. USA., 86, 4525-4529 (1989), and Cir. Res., 73, 269-275 (1993)].
Still further, the relationship between activation of NHE and inflammation has been reported [Am. J. Physiol., 267, C1623-C1632 (1994)], and the NHE inhibitor is useful as an agent for treating or preventing diseases caused by infiltration of leukocytes associated with enhanced NHE activity, such as inflammation.
As stated above, it has been known that NHE activity is enhanced in various states of NHE. The NHE activity can easily be measured by using a strong NHE inhibitor to easily obtainable cells such as platelets, erythrocytes and leukocytes. That is, the NHE inhibitor is also useful as a diagnostic agent for hypertension, diseases caused by cell growth, diabetes and the like.
Amiloride derivatives containing a guanidinocarbonyl group have been used in animal tests as an NHE inhibitor so far. It has been reported that these compounds suppress simultaneously Na.sup.+ (sodium ion) channels and an Na.sup.+ /Ca.sup.+ (sodium ion/calcium ion) exchanger in concentrations in which they suppress NHE, and with respect to the NHE inhibitory activity, IC.sub.50 (50% inhibitory concentration) is approximately 100 .mu.M which is not satisfactory [J. Membrane, Biol., 105, 1-21 (1988)]. The above-mentioned amiloride derivatives and benzoylguanidine derivatives [JP A 3-106858 (Family: EP416499), and the like; hereinafter "JP A" means Publication of Japanese Patent Application] which are monocyclic compounds have been known as an NHE inhibitor. On the other hand, isoquinoline derivatives [JP A 6-211799 (Family: EP590455)], indole derivatives [JP A 7-10839 (Family: EP622356)] and quinoline derivatives (EP682017) have been known as compounds having a fused ring. The quinoline derivatives described in EP682017 are compounds containing a guanidinocarbonyl group in the 3-position. With respect to the NHE inhibitory activity, IC.sub.50 is several micromoles, and it is not satisfactory.
The present invention is to provide compounds which have strong NHE inhibitory activity and which are useful as an agent for preventing or treating various diseases caused by hyperfunction of NHE and as a diagnostic agent.